Tenofovir (TFV) has become a cornerstone of HIV treatment since its approval for use in 2001 as tenofovir disoproxil fumarate (TDF). In 2015 the World Health Organization maintained its recommendation that TDF, which is metabolized into TFV in vivo, be part of the preferred first-line regimen for antiretroviral therapy to treat HIV patients (World Health Organization. Fact Sheet: HIV treatment and care: what's new in HIV treatment; 2015). In addition, the WHO recommends pre-exposure prophylaxis (PrEP) therapies containing TFV-derived medications be deployed to prevent the transmission of the virus among high-risk populations in both high- and low-resource settings (Baggaley, R.; Dalal, S.; Johnson, C.; Macdonald, V.; Mameletzis, I.; Rodolph, M.; Figueroa, C.; Samuelson, J.; Verster, A.; Doherty, M.; Hirnschall, G. J. Int. AIDS Soc. 2016, 19 (1), 21348). As a result of these recommendations and the development of new formulations, such as tenofovir alafenamide (TAF), TFV will likely remain one of the most important tools for the treatment and prevention of HIV.
The number of people accessing antiretroviral medications to manage their HIV infections has risen to over 18 million worldwide as of June 2016 (Joint United Nations Programmed on HIV/AIDS(UNAIDS) Fact Sheet: Global HIV statistics; 2016). Around 10 million of these people are on treatment regimens containing TFV (Clinton Health Access Initiative. ARV Market Report; 2016). With the increasing accessibility and efficacy of these medications it becomes more important to ensure that drug regimens are being properly managed by HIV patients. Mismanagement of HIV drug regimens routinely results in a heightened risk of transmission, decreased patient health and quality of life, and an increase in the incidence of HIV drug resistance (AIDSinfo: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents; 2017). The WHO cites poor adherence as the main reason for suboptimal clinical benefits managing chronic illnesses such as HIV/AIDS (Dunbar-Jacob, J.; Erlen, J. A.; Schlenk, E. A.; Ryan, C. M.; Sereika, S. M.; Doswell, W. M. Annu. Rev. Nurs. Res. 2000, 18, 48-90). Poor adherence habits have already resulted in a large growth in TFV-resistant HIV strains that threaten to diminish the effectiveness of the drug (The TenoRes Study Group. Lancet Infect. Dis. 2016, 16 (5), 565-575). As a result, it is critical that clinicians monitor the adherence of HIV patients to their prescribed treatment regimens.
To manage HIV infections and keep viral loads low patients must be at least 80-95% adherent to their antiretroviral treatments (Paterson, D. L.; Swindells, S.; Mohr, J.; Brester, M.; Vergis, E. N.; Squier, C.; Wagener, M. M.: Singh, N. Ann. Intern. Med. 2000, 133 (1), 21-30; Montaner, J. S.; Reiss, P.; Cooper, D.; Vella, S.; Harris, M.; Conway, B.; Wainberg, M. A.; Smith, D.; Robinson, P.; Hall, D.; Myers, M.; Lange, J. M. JAMA 1998, 279 (12), 930-937; Bangsberg, D. R.; Hecht, F. M.; Charlebois, E. D.; Zolopa, a R.; Holodniy, M.; Sheiner, L.; Bamberger, J. D.; Chesney, M. a; Moss, a. AIDS 2000, 14 (4), 357-366; Viswanathan, S.; Detels, R.; Mehta, S. H.; Macatangay, B. J. C.; Kirk, G. D.; Jacobson, L. P. AIDS Behay. 2015, 19 (4), 601-611). Studies have shown that many populations of patients do not demonstrate adequate adherence rates (McNabb, J. J.; Nicolau, D. P.; Stoner, J. a; Ross, J. AIDS 2003, 17 (12), 1763-1767; Liu, H.; Golin, C. E.; Miller, L. G.; Hays, R. D.; Beck, C. K.; Sanandaji, S.; Christian, J.; Maldonado, T.; Duran, D.; Kaplan, A. H.; Wenger, N. S.; Inhibitors, H. I. V. P. Ann. Intern. Med. 2001, 134 (10), 968-977; Arnsten, J. H.; Demas, P. A.; Farzadegan, H.; Grant, R. W.; Gourevitch, M. N.; Chang, C. J.; Buono, D.; Eckholdt, H.; Howard, A. A.; Schoenbaum, E. E. Clin. Infect. Dis. 2001, 33 (8), 1417-1423). There are many factors that affect patients and diminish their adherence rates: complexity of regimen, side effects, and patient psychological factors among others (Carr, a. Clin. Infect. Dis. 2000, 30 Suppl 2, S135-42; Chesney, M. A. Improv. Manag. HIV Dis. 1997, 5 (12); Malow R, Devieux J G, Rosenberg R, et al. Psychol AIDS Exch. 2001, 30, 23-26; d'Arminio Monforte, A.; Lepri, A. C.; Rezza, G.; Pezzotti, P.; Antinori, A.; Phillips, A. N.; Angarano, G.; Colangeli, V.; De Luca, A.; Ippolito, G.; Caggese, L.; Soscia, F.; Filice, G.; Gritti, F.; Narciso, P.; Tirelli, U.; Moroni, M. Aids 2000, 14 (5), 499-507; Kaul, D. R.; Cinti, S. K.; Carver, P. L.; Kazanjian, P. H. Pharmacotherapy 1999, 19, 281-298). Fortunately, there are many intervention options available that have been shown to improve adherence behaviors and health outcomes (World Health Organization. Adherence to long-term therapies: Evidence for action; 2003; Vol. 2).
In addition to HIV, tuberculosis (TB) remains a major public health concern more than 60 years after the first effective antibiotics were developed. A prime contributing factor globally to its persistence is inconsistent patient compliance with the 6-9 month first line drug treatment regimen. Non-compliance contributes to morbidity, mortality and rise of multiply drug resistant (MDR) TB. Non-adherence prolongs the infectious state of the disease, leading to more cases. It is more difficult to achieve high adherence in patients with latent TB infection (LTBI) who are not suffering symptoms. Directly Observed Therapy Short-course (DOTS), wherein, the ingestion of each medication dose is observed in-person by healthcare personnel, or more recently over a video feed, is still supported by the WHO as a TB treatment compliance method. However, several studies and meta-analyses conclude that DOTS alone does not increase rates of completion of therapy. While 33% of the world population is infected with the tuberculosis mycobacteria, most of these people will never develop cases of active TB. A small portion of this population, who are at high risk for developing active TB because they have weakened immune systems (due to HIV or other infections), are treated for latent TB each year. Of these, the vast majority receive a monotherapy of isoniazid (INH).
People co-infected with HIV and TB are some of the most vulnerable patients worldwide. TB is the number one cause of death in HIV infected people. HIV patients with LTBI must be treated for both infections and co-infected patients are less likely to adhere to therapy. TB is, for the most part, a curable disease, and HIV can be successfully managed with highly active antiretroviral therapy (ART).
Current methods for tracking adherence behaviors are mostly indirect such as pill counting, electronic drug monitoring, and patient self-reporting (AIDSinfo: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.; 2017). Pill counting and electronic monitoring are limited in their deployment and self-reporting, the most widely used method, is prone to overestimation (Waterhouse, D. M.; Calzone, K. A.; Mele, C.; Brenner, D. E. J. Clin. Oncol. 1993, 11 (6), 1189-1197; Gao, X.; Nau, D. P. Ann Pharmacother 2000, 34 (10), 1117-1122). Current direct methods to measure drug levels in patient samples generally require expensive equipment (Simiele, M.; Carcieri, C.; De Nicoló, A.; Ariaudo, A.; Sciandra, M.; Calcagno, A.; Bonora, S.; Di Perri, G.; D'Avolio, A. J. Pharm. Biomed. Anal. 2015, 114, 8-11) that is not easily accessible in resource-limited settings where the need is greatest.
There is therefore a need for compositions, devices and assays that can facilitate objective monitoring of HIV and TB treatment adherence habits in all settings without the need for expensive equipment or long turnaround times allowing clinicians to intervene in cases of noncompliance and improve overall patient outcomes. A cheap and effective monitoring technology that does not rely on health or community workers to see the patient every day and relies on both the provider and the patient to participate, has the potential to provide an effective yet inexpensive method for ensuring compliance.